ES250249A1 - 9, 11-dihalogeno steroids - Google Patents
9, 11-dihalogeno steroidsInfo
- Publication number
- ES250249A1 ES250249A1 ES0250249A ES250249A ES250249A1 ES 250249 A1 ES250249 A1 ES 250249A1 ES 0250249 A ES0250249 A ES 0250249A ES 250249 A ES250249 A ES 250249A ES 250249 A1 ES250249 A1 ES 250249A1
- Authority
- ES
- Spain
- Prior art keywords
- prepared
- dione
- methyl
- hydroxy
- reacting
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 150000003431 steroids Chemical class 0.000 title 1
- 229910052736 halogen Inorganic materials 0.000 abstract 9
- 238000000034 method Methods 0.000 abstract 9
- -1 nitrosyl halide Chemical class 0.000 abstract 9
- 150000002367 halogens Chemical group 0.000 abstract 7
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 abstract 6
- 150000001875 compounds Chemical class 0.000 abstract 5
- 150000002148 esters Chemical class 0.000 abstract 5
- OSVMTWJCGUFAOD-KZQROQTASA-N formestane Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1O OSVMTWJCGUFAOD-KZQROQTASA-N 0.000 abstract 5
- 239000007858 starting material Substances 0.000 abstract 5
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 abstract 4
- LPXQXCAQINZRGR-UHFFFAOYSA-N CC(C=C1)=CC=C1I.Cl.Cl Chemical compound CC(C=C1)=CC=C1I.Cl.Cl LPXQXCAQINZRGR-UHFFFAOYSA-N 0.000 abstract 4
- 238000006243 chemical reaction Methods 0.000 abstract 4
- 230000007062 hydrolysis Effects 0.000 abstract 4
- 238000006460 hydrolysis reaction Methods 0.000 abstract 4
- 239000000203 mixture Substances 0.000 abstract 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 abstract 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 abstract 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 abstract 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 abstract 3
- 239000002253 acid Substances 0.000 abstract 3
- 239000003795 chemical substances by application Substances 0.000 abstract 3
- 238000006356 dehydrogenation reaction Methods 0.000 abstract 3
- 230000032050 esterification Effects 0.000 abstract 3
- 238000005886 esterification reaction Methods 0.000 abstract 3
- 230000026030 halogenation Effects 0.000 abstract 3
- 238000005658 halogenation reaction Methods 0.000 abstract 3
- 150000003128 pregnanes Chemical class 0.000 abstract 3
- 238000002360 preparation method Methods 0.000 abstract 3
- 239000000047 product Substances 0.000 abstract 3
- 229960003387 progesterone Drugs 0.000 abstract 3
- 239000000186 progesterone Substances 0.000 abstract 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 abstract 2
- 241000025946 Chaetoceros simplex Species 0.000 abstract 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 abstract 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract 2
- QZRGKCOWNLSUDK-UHFFFAOYSA-N Iodochlorine Chemical compound ICl QZRGKCOWNLSUDK-UHFFFAOYSA-N 0.000 abstract 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 abstract 2
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 abstract 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 abstract 2
- 229910052801 chlorine Inorganic materials 0.000 abstract 2
- 239000000460 chlorine Substances 0.000 abstract 2
- 230000002140 halogenating effect Effects 0.000 abstract 2
- 229910000040 hydrogen fluoride Inorganic materials 0.000 abstract 2
- 230000003301 hydrolyzing effect Effects 0.000 abstract 2
- 230000033444 hydroxylation Effects 0.000 abstract 2
- 238000005805 hydroxylation reaction Methods 0.000 abstract 2
- 229910052744 lithium Inorganic materials 0.000 abstract 2
- VXWPONVCMVLXBW-UHFFFAOYSA-M magnesium;carbanide;iodide Chemical compound [CH3-].[Mg+2].[I-] VXWPONVCMVLXBW-UHFFFAOYSA-M 0.000 abstract 2
- 238000004519 manufacturing process Methods 0.000 abstract 2
- 230000002906 microbiologic effect Effects 0.000 abstract 2
- 230000003647 oxidation Effects 0.000 abstract 2
- 238000007254 oxidation reaction Methods 0.000 abstract 2
- 230000001590 oxidative effect Effects 0.000 abstract 2
- 238000010992 reflux Methods 0.000 abstract 2
- 239000004289 sodium hydrogen sulphite Substances 0.000 abstract 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 abstract 2
- 235000009518 sodium iodide Nutrition 0.000 abstract 2
- 239000000126 substance Substances 0.000 abstract 2
- SMIDAKVWLSXXKQ-GOMVOUAHSA-N (5S,6R,8R,9S,10R,13S,14S,17R)-17-acetyl-17-bromo-5-hydroxy-6,10,13-trimethyl-1,2,4,6,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-3-one Chemical compound O[C@]12[C@@H](C[C@H]3[C@@H]4CC[C@](C(C)=O)([C@]4(CC[C@@H]3[C@]2(CCC(C1)=O)C)C)Br)C SMIDAKVWLSXXKQ-GOMVOUAHSA-N 0.000 abstract 1
- YJDYCULVYZDESB-HKQXQEGQSA-N (5r,8r,9s,10s,13s,14s)-10,13-dimethyl-1,2,3,4,5,6,7,8,9,11,12,14,15,16-tetradecahydrocyclopenta[a]phenanthren-17-one Chemical class C1CCC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC[C@H]21 YJDYCULVYZDESB-HKQXQEGQSA-N 0.000 abstract 1
- QUKZBUCPOSYYFO-FPRQENGNSA-N (5r,8r,9s,10s,13s,14s)-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-ol Chemical class C1CCC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)O)[C@@H]4[C@@H]3CC[C@H]21 QUKZBUCPOSYYFO-FPRQENGNSA-N 0.000 abstract 1
- SMBOUCWJBJUHDR-CTVGIFIDSA-N (6S,8S,10R,13S,14S,17R)-17-(2-fluoroacetyl)-17-hydroxy-6,10,13-trimethyl-2,6,7,8,12,14,15,16-octahydro-1H-cyclopenta[a]phenanthren-3-one Chemical compound C[C@H]1C[C@H]2[C@@H]3CC[C@](C(CF)=O)([C@]3(CC=C2[C@]2(CCC(C=C12)=O)C)C)O SMBOUCWJBJUHDR-CTVGIFIDSA-N 0.000 abstract 1
- OTSPHSRSIAIVOY-JRMUFCLDSA-N (6s,8s,10r,13s,14s,17r)-17-acetyl-17-hydroxy-6,10,13-trimethyl-2,6,7,8,12,14,15,16-octahydro-1h-cyclopenta[a]phenanthren-3-one Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1C2=CC[C@]2(C)[C@@](O)(C(C)=O)CC[C@H]21 OTSPHSRSIAIVOY-JRMUFCLDSA-N 0.000 abstract 1
- LTLZKGMWZNNLBR-CTVGIFIDSA-N (6s,8s,10r,13s,14s,17r)-17-hydroxy-17-(2-hydroxyacetyl)-6,10,13-trimethyl-2,6,7,8,12,14,15,16-octahydro-1h-cyclopenta[a]phenanthren-3-one Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1C2=CC[C@]2(C)[C@@](O)(C(=O)CO)CC[C@H]21 LTLZKGMWZNNLBR-CTVGIFIDSA-N 0.000 abstract 1
- PGWDPYGLSQZOMQ-NMKBPFOZSA-N (8s,10s,13r,14s,17s)-17-ethyl-10,13-dimethyl-6,7,8,12,14,15,16,17-octahydro-3h-cyclopenta[a]phenanthrene Chemical compound C1C=C[C@]2(C)C3=CC[C@]4(C)[C@@H](CC)CC[C@H]4[C@@H]3CCC2=C1 PGWDPYGLSQZOMQ-NMKBPFOZSA-N 0.000 abstract 1
- KTDNJCHWPZHOFC-XFNFOBRPSA-N (8s,9s,10s,13r,14s,17r)-17-(2-fluoroethyl)-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthrene Chemical compound C1CCC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)CCF)[C@@H]4[C@@H]3CCC21 KTDNJCHWPZHOFC-XFNFOBRPSA-N 0.000 abstract 1
- POYNBBXYPFXQRC-XFNFOBRPSA-N (8s,9s,10s,13r,14s,17r)-17-(2-iodoethyl)-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthrene Chemical class C1CCC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)CCI)[C@@H]4[C@@H]3CCC21 POYNBBXYPFXQRC-XFNFOBRPSA-N 0.000 abstract 1
- AUWGBTUZQWKWRS-WISGCMSASA-N 1-[(3S,8S,9S,10R,13S,14S,16R,17S)-16-ethyl-3-hydroxy-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl]ethanone Chemical compound O[C@@H]1CC2=CC[C@H]3[C@@H]4C[C@H]([C@H](C(C)=O)[C@]4(CC[C@@H]3[C@]2(CC1)C)C)CC AUWGBTUZQWKWRS-WISGCMSASA-N 0.000 abstract 1
- RSRDWHPVTMQUGZ-OZIWPBGVSA-N 1-[(8r,9s,10s,13s,14s,17s)-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]ethanone Chemical class C1CC2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RSRDWHPVTMQUGZ-OZIWPBGVSA-N 0.000 abstract 1
- YLFRRPUBVUAHSR-RRPFGEQOSA-N 16,17-didehydropregnenolone Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC=C(C(=O)C)[C@@]1(C)CC2 YLFRRPUBVUAHSR-RRPFGEQOSA-N 0.000 abstract 1
- TZJKBFRUMZLUME-UHFFFAOYSA-N 2,2-dibromo-1,4-dioxane Chemical compound BrC1(Br)COCCO1 TZJKBFRUMZLUME-UHFFFAOYSA-N 0.000 abstract 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 abstract 1
- 241000134727 Agromyces mediolanus Species 0.000 abstract 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 abstract 1
- 229910021630 Antimony pentafluoride Inorganic materials 0.000 abstract 1
- 241000223211 Curvularia lunata Species 0.000 abstract 1
- 239000005977 Ethylene Substances 0.000 abstract 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 abstract 1
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 abstract 1
- CRRKVZVYZQXICQ-RJJCNJEVSA-N Pregnenolone acetate Chemical compound C([C@@H]12)C[C@]3(C)[C@@H](C(C)=O)CC[C@H]3[C@@H]1CC=C1[C@]2(C)CC[C@H](OC(=O)C)C1 CRRKVZVYZQXICQ-RJJCNJEVSA-N 0.000 abstract 1
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Natural products C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 abstract 1
- 241000235546 Rhizopus stolonifer Species 0.000 abstract 1
- DQHKOPGHSPUDFM-ABVATSDPSA-N [(3S,8R,9S,10R,13S,14S)-17-(1-acetyloxyethylidene)-10,13-dimethyl-1,2,3,4,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-3-yl] acetate Chemical compound C(C)(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CCC(=C(C)OC(C)=O)[C@]4(CC[C@@H]3[C@]2(CC1)C)C DQHKOPGHSPUDFM-ABVATSDPSA-N 0.000 abstract 1
- LGMLPGOANOZALY-KIYFCUGLSA-N [(3S,8R,9S,10R,13S,14S,17R)-17-acetyl-17-chloro-10,13-dimethyl-1,2,3,4,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-3-yl] acetate Chemical compound C(C)(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@](C(C)=O)([C@]4(CC[C@@H]3[C@]2(CC1)C)C)Cl LGMLPGOANOZALY-KIYFCUGLSA-N 0.000 abstract 1
- PYBGGSNABBXWHO-QJCZYOOHSA-N [(3S,8S,9S,10R,13S,14S,16R,17S)-17-acetyl-5,6-dichloro-10,13,16-trimethyl-1,2,3,4,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-3-yl] acetate Chemical compound C(C)(=O)O[C@@H]1CC2(C(C[C@H]3[C@@H]4C[C@H]([C@H](C(C)=O)[C@]4(CC[C@@H]3[C@]2(CC1)C)C)C)Cl)Cl PYBGGSNABBXWHO-QJCZYOOHSA-N 0.000 abstract 1
- SFNSGHUMGYWJGF-AWGTVLFOSA-N [(3s,8s,9s,10r,13s,14s,16r,17s)-17-acetyl-10,13,16-trimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-yl] acetate Chemical compound C1C=C2C[C@@H](OC(C)=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@@H](C)[C@H](C(C)=O)[C@@]1(C)CC2 SFNSGHUMGYWJGF-AWGTVLFOSA-N 0.000 abstract 1
- CDKFWIMBZAUBRS-UHFFFAOYSA-M [I-].CC[Mg+] Chemical compound [I-].CC[Mg+] CDKFWIMBZAUBRS-UHFFFAOYSA-M 0.000 abstract 1
- 230000021736 acetylation Effects 0.000 abstract 1
- 238000006640 acetylation reaction Methods 0.000 abstract 1
- 150000007513 acids Chemical class 0.000 abstract 1
- 125000004423 acyloxy group Chemical group 0.000 abstract 1
- 125000000217 alkyl group Chemical group 0.000 abstract 1
- 230000029936 alkylation Effects 0.000 abstract 1
- 238000005804 alkylation reaction Methods 0.000 abstract 1
- 125000005530 alkylenedioxy group Chemical group 0.000 abstract 1
- VBVBHWZYQGJZLR-UHFFFAOYSA-I antimony pentafluoride Chemical compound F[Sb](F)(F)(F)F VBVBHWZYQGJZLR-UHFFFAOYSA-I 0.000 abstract 1
- 125000004429 atom Chemical group 0.000 abstract 1
- 230000031709 bromination Effects 0.000 abstract 1
- 238000005893 bromination reaction Methods 0.000 abstract 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract 1
- 229910052794 bromium Inorganic materials 0.000 abstract 1
- 239000006227 byproduct Substances 0.000 abstract 1
- 230000015556 catabolic process Effects 0.000 abstract 1
- 239000003153 chemical reaction reagent Substances 0.000 abstract 1
- 238000004587 chromatography analysis Methods 0.000 abstract 1
- 230000000382 dechlorinating effect Effects 0.000 abstract 1
- 238000006731 degradation reaction Methods 0.000 abstract 1
- 230000018044 dehydration Effects 0.000 abstract 1
- 238000006297 dehydration reaction Methods 0.000 abstract 1
- 238000007269 dehydrobromination reaction Methods 0.000 abstract 1
- 230000000694 effects Effects 0.000 abstract 1
- 238000006345 epimerization reaction Methods 0.000 abstract 1
- 150000002118 epoxides Chemical class 0.000 abstract 1
- 239000012025 fluorinating agent Substances 0.000 abstract 1
- 150000004820 halides Chemical class 0.000 abstract 1
- 150000008282 halocarbons Chemical class 0.000 abstract 1
- 229910001385 heavy metal Inorganic materials 0.000 abstract 1
- 229910003439 heavy metal oxide Inorganic materials 0.000 abstract 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- XRURPHMPXJDCOO-UHFFFAOYSA-N iodine heptafluoride Chemical compound FI(F)(F)(F)(F)(F)F XRURPHMPXJDCOO-UHFFFAOYSA-N 0.000 abstract 1
- KSRHWBLHVZJTKV-UHFFFAOYSA-N iodobenzene dichloride Chemical compound ClI(Cl)C1=CC=CC=C1 KSRHWBLHVZJTKV-UHFFFAOYSA-N 0.000 abstract 1
- 238000002955 isolation Methods 0.000 abstract 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 abstract 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 abstract 1
- 150000007522 mineralic acids Chemical class 0.000 abstract 1
- VDCLSGXZVUDARN-UHFFFAOYSA-N molecular bromine;pyridine;hydrobromide Chemical compound Br.BrBr.C1=CC=NC=C1 VDCLSGXZVUDARN-UHFFFAOYSA-N 0.000 abstract 1
- VBTQNRFWXBXZQR-UHFFFAOYSA-N n-bromoacetamide Chemical compound CC(=O)NBr VBTQNRFWXBXZQR-UHFFFAOYSA-N 0.000 abstract 1
- 150000007530 organic bases Chemical group 0.000 abstract 1
- 229910052700 potassium Inorganic materials 0.000 abstract 1
- 239000011591 potassium Substances 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- 238000007127 saponification reaction Methods 0.000 abstract 1
- 239000002904 solvent Substances 0.000 abstract 1
- 238000010561 standard procedure Methods 0.000 abstract 1
- 230000000707 stereoselective effect Effects 0.000 abstract 1
- FQFKTKUFHWNTBN-UHFFFAOYSA-N trifluoro-$l^{3}-bromane Chemical compound FBr(F)F FQFKTKUFHWNTBN-UHFFFAOYSA-N 0.000 abstract 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
The invention comprises (1) a process for the production of 9a ,11b -dihalogeno-pregnanes and -androstanes by reacting the corresponding 9,11-dehydro compounds with a halogenating agent, or by reacting the corresponding 9a -halogeno-11a -hydroxy compound with a sulphonating agent to form the 11a -sulphonic ester and reacting this with a halide, or by reacting the corresponding 9a -halogeno-11a -amino compound with a nitrosyl halide, or by treating the corresponding 9a -halogeno-11b -amino compound first with an alkyl nitrite and then with a hydrohalic acid and (2) as new compounds, the products of (1) which contain a 3-keto group and, in the case of the pregnanes, also a 20-keto group. The process may be applied to 3-keto-9(11)- androstenes and 3,20-diketo-9(11)-pregnenes and their 19-nor-analogues which may optionally contain D 1-, D 4- or D 1,4-double bonds and/or lower alkyl, hydroxy, acyloxy, alkylenedioxy, and/or halogen substituents in the nucleus or side chains, particularly in positions 2, 6, 16, 17 and 21. The halogenating agent may be (1) molecular halogen such as chlorine or bromine (2) molecular halogen donors such as pyridinium bromide perbromide, dioxan dibromide, iodobenzene dichloride and p-iodotoluene dichloride (3) halogen halides such as iodine monochloride (4) mixtures of reagents comprising a positive halogen donor such as molecular halogen, a halogen halide or a compound such as N-chlor- or N-iodosuccinimide, N-bromoacetamide or dimethyl-N,N-dibromohydantoin together with a halogen ion of electronegativity equal to or greater than that of the positive halogen donor, which may be supplied by a salt such as a lithium or potassium halide or a hydrohalic acid or mixtures thereof and (5) fluorinating agents such as heavy metal polyfluorides or mixtures of heavy metal oxides or idosobenzene diacetate with hydrogen fluoride, antimony pentafluoride, iodine heptafluoride or bromine trifluoride. In these halogenation processes the more electronegative halogen goes to the 11-position. In a preferred process the halogenation is conducted in a halogenated hydrocarbon solvent in presence of a tertiary organic base, whereby the production of unwanted by-products is minimized. To effect halogenation wherein the more electronegative atom is attached at position 9 the processes utilising a sulphonate ester, a nitrosyl halide or an alkyl nitrite may be used. In the sulphonation process a 21-hydroxyl group must be previously protected by conversion to a 21-ester. Examples illustrate all the above processes and the D 1-dehydrogenation (using C. simplex), chemical or microbiological hydrolysis of 21-esters and esterification of 21-ols with mono- or di-carboxylic acids, sulphonic acids or inorganic acids, hydrolysis of 16-esters and preparation of 16a ,17a -alkylenedioxy derivatives from 16a ,17a -diols, degradation of the 17-side chain in 20-keto-pregnanes to give the corresponding androstan-17-ones, the reduction of these to androstan-17-ols by chemical or microbiological, e.g. using C. cerevisiae, methods and esterification of the 17-ols and esterification of 17-hydroxy groups in pregnane compounds, of the 9a ,11b -dihalogeno products. Reference is also made to oxidation, hydroxylation and alkylation of these products, and to the oxidation of 3-hydroxy- 9a ,11b - dihalogeno-17(20), 20(21)-bismethylenedioxy pregnanes to the 3-ketones and subsequent preparation of the D 4- and D 1,4-compounds by bromination and dehydrobromination or the action of C. simplex and removal of the bismethylenedioxy group. D 9(11)-Steroid starting materials are prepared by standard methods from the corresponding 11- hydroxylated compounds p sometimes with isolation of the 11a -hydroxy sulphonate esters or D 1,4,9(11)-steroid starting materials are obtained by D 1-dehydrogenation of the corresponding D 4,9(11)-steroids. 9a -Halo- 11b - hydroxysteroid starting materials are prepared from the corresponding 9b ,11b -oxido-steroids, and may subsequently be oxidized to 9a -halo-11-keto-steroids which on stereospecific reduction, if necessary with protection of a 3- and/or 20-keto group by conversion to a 3- or 3,20-bis-ethylene ketal and/or protection of a 20-keto group in a 17-hydroxy compound by conversion to a 17(20),20(21)-bis-methylenedioxy group, gives a 9a -halo-11a -hydroxy-steroid. 11a -Hydroxy steroid starting materials are prepared by hydroxylation of the 11-unsubstituted compounds using C. lunata or R. nigricans. 9a -Fluoro- 3a -hydroxy-11(a and b )amino-17a (20),20(21)- bis-methylenedioxypregnanes are prepared by reacting 9a -fluoro-cortisone with formaldehyde to give 9a -fluoro-17(20), 20(21)- bis-methylenedioxy- 4-pregnene-3,11-dione, reducing this to give 9a -fluoro-17(20), 20(21)- bismethylenedioxypregnane -3-ol-11-one, treating this with hydroxylamine to give the corresponding 11-oximino-steroid and reducing this to give a mixture of the required epimers, which are separated by chromatography. 1,4,9(11)- Pregnatriene- 17a ,21- diol- 3,20-dione is prepared by saponification of the 21-acetate. 6b -Methyl-19-nor- 4-androsten-11b -ol-3,17-dione is prepared by reacting 5a ,6a -epoxy-19-nor-androstan- 11b -ol-3,17-dione 3,17-bis-ethyleneketal with methyl magnesium bromide to give 6b -methyl-19-nor-androstane-5a ,11b -diol-3,17-dione 3,17-bismethyleneketal, hydrolysing this to 6b -methyl-19-nor-androstane-5a ,11b -diol-3,17-dione and refluxing this with sodium hydroxide. 1,4,9(11)-Androstatrien-17b -ol-3-one is prepared by reduction of the 3,17-dione and is subsequently converted to various esters. 6a -Fluoro-17a -methyl-9(11)- androsten-17b -ol-3-one is prepared by reaction of the corresponding D 4-compound with lithium in liquid ammonia. 6a -Methyl-9(11)-androsten-17b -ol-3-one is prepared similarly and is converted to the 17-propionate. 6a -Fluoro-19-nor-9(11)-androsten-3,17-dione is prepared similarly from the corresponding D 4-compound, itself prepared by dehydrogenation of of the 11b -ol. 17a -Ethyl-9(11)- androsten- 17b -ol-3-one is prepared by converting 9(11)-androstene-3,17-dione to the 3-pyrrolidylenamine and reacting this with ethyl magnesium bromide with subsequent hydrolysis. 21-Fluoro-pregnane starting materials are prepared from the 21-iodo-pregnanes, which are prepared either from the 21-ols via the 21-tosylates or from the 21-unsubstituted-pregnanes. 17a -Acetoxy-4,9(11)- pregnadiene-3,20-dione is prepared by acetylation of the 17-ol. The corresponding 1,4,9(11)-pregnatriene is prepared similarly, the 17-ol being prepared by reacting 17a ,21-dihydroxy- 1,4,9(11)- pregnatriene-3,20-dione (prepared by hydrolysis of the 21-acetate) first with tosyl chloride, then sodium iodide and then sodium bisulphite and acetic acid. 17a -Methyl-4,9(11)-pregnadiene-3,20-dione is prepared similarly from the 21-tosylate, itself prepared from the 21-ol. 17a -Chloro-progesterone is prepared by reacting 3b -acetoxy- 5-pregnene- 20-one with acetic anhydride to give 5,17(20)-pregnadiene-3b ,20-diol diacetate, reacting this with chlorine to give 3b -acetoxy-5a ,6b ,17a -trichloroallopregnan-20-one, dehalogenating this to 3b -acetoxy-17a - chloro-5-pregnen-20-one and subjecting this to a culture of F. dehydrogenans. Esters of 17a -hydroxy-21-fluoro- 4,9(11)-pregnadiene-3,20-dione are prepared from the 17-ol, itself prepared from 17a -hydroxy-21-iodo-4,9(11)-pregnadiene-3,20-dione (prepared from the 21-bromo compound), which is also converted into the 17-acetate. 6a -Methyl-17a -hydroxy- 4,9(11)-pregnadiene-3,20-dione is prepared by dehydrating 6a -methylhydrocortisone acetate to give 6a -methyl-17a ,21-dihydroxy- 4,9(11)-pregnadiene-3,20-dione 21-acetate, hydrolysing this to the 21-ol and reacting this with tosyl chloride, then sodium iodide and then sodium bisulphite, and is converted to various 17-esters. The corresponding 6a -fluoro compound is prepared by dehydration of the 11-ol and is converted to the 17-acetate. 6b ,17a -Dimethyl progesterone is prepared by converting 17a -methyl-progesterone to the 3,20-bisethyleneketal, converting this to the 5a ,6a -epoxide, reacting this with methyl magnesium iodide to give 5a -hydroxy-6b ,17a -dimethylpregnane-3,20-dione and dehydrating this. The corresponding 6b -fluoro compounds are similarly prepared via the epoxide and hydrogen fluoride. The corresponding 17a -bromo compounds are prepared similarly. 6a ,17a -Dimethyl- 4,9(11)- pregnadiene-3,20-dione is prepared by epimerization of the 6b -isomer. The corresponding 6a -fluoro compound is prepared similarly. 6a -Methyl-17a - bromoprogesterone is prepared from 5a -hydroxy-6b -methyl-17a -bromo-pregnane-3,20-dione and refluxing ethanol containing hydrochloric acid. The corresponding 6a -fluoro compound is prepared similarly. Esters of 6a -methyl-17a -hydroxy-21-fluoro-4,9(11)-pregnadiene-3,20-dione are prepared from the 17-ol. The preparation of esters of other 17-ols referred to above and below is also described. 16a -Methyl- 17a -hydroxyprogesterone is prepared by chlorinating 3b -acetoxy-16a -methyl-5-pregnen-20-one to give 3b -acetoxy-5,6-dichloro-16a -methyl-pregnan-20-one, converting this to 3b ,17a -dihydroxy-5,6-dichloro-16a -methyl-pregnan-20-one, oxidizing this to the 3,20-dione, dechlorinating this to 16a -methyl- 17a -hydroxy- 5-pregnene- 3,20-dione and isomerizing this. 16a -Ethyl-progesterone is prepared by reacting 3b -hydroxy- 5,16-pregnadien- 20-one wih ethyl magnesium iodide to give 3b -hydroxy-16a -ethyl-5-pregnen-20-one and oxidizing this by the Oppenauer method. 6a ,16a -Dimethyl- 11a ,17a -dihydroxyprogesterone is prepared by converting 11a ,17a -dihydroxy-16a -methyl-progesterone to the 3,20-bis-ethyleneketal, converting this to 5a ,6a -epoxy- 11a ,17a - dihydroxy- 16a - methylpregnane-3, 20-dione 3,20-bis-ethyleneketal, reacting this wih methyl magnesium iodide to give 5a ,11a ,17a - trihydroxy- 6b ,16a -dimeth
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US743492A US2894963A (en) | 1958-06-20 | 1958-06-20 | 9,11-dihalogeno-4-pregnenes and 1,4-pregnadienes |
CA775651 | 1959-05-30 |
Publications (1)
Publication Number | Publication Date |
---|---|
ES250249A1 true ES250249A1 (en) | 1960-01-16 |
Family
ID=25673299
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ES0250249A Expired ES250249A1 (en) | 1958-06-20 | 1959-06-19 | 9, 11-dihalogeno steroids |
Country Status (7)
Country | Link |
---|---|
BE (1) | BE579900A (en) |
CH (1) | CH386415A (en) |
DK (1) | DK118874B (en) |
ES (1) | ES250249A1 (en) |
FR (1) | FR564M (en) |
GB (2) | GB928301A (en) |
NL (1) | NL106036C (en) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3397213A (en) * | 1966-01-12 | 1968-08-13 | Squibb & Sons Inc | 12 methyl-9, 11-dihaloprogesterones |
FR2342738A1 (en) * | 1976-03-02 | 1977-09-30 | Roussel Uclaf | NEW HALOGEN DERIVATIVES OF THE 16A-METHYL PREGNANE SERIES |
DK2278978T3 (en) | 2008-05-28 | 2015-09-21 | Reveragen Biopharma Inc | NON-HORMONAL STEROID MODULATORS OF NF-KB FOR TREATMENT OF DISEASE |
EP2556083A4 (en) | 2010-04-05 | 2013-12-04 | Validus Biopharma Inc | Non-hormonal steroid modulators of nf- kappa b for treatment of disease |
US10799514B2 (en) | 2015-06-29 | 2020-10-13 | Reveragen Biopharma, Inc. | Non-hormonal steroid modulators of NF-kappa beta for treatment of disease |
US11382922B2 (en) | 2019-03-07 | 2022-07-12 | Reveragen Biopharma, Inc. | Aqueous oral pharmaceutical suspension compositions |
-
1959
- 1959-06-11 GB GB20033/59A patent/GB928301A/en not_active Expired
- 1959-06-11 GB GB43100/61A patent/GB928302A/en not_active Expired
- 1959-06-18 CH CH7465759A patent/CH386415A/en unknown
- 1959-06-18 NL NL240357A patent/NL106036C/xx active
- 1959-06-19 DK DK220659AA patent/DK118874B/en unknown
- 1959-06-19 ES ES0250249A patent/ES250249A1/en not_active Expired
- 1959-06-20 BE BE579900A patent/BE579900A/en unknown
-
1960
- 1960-08-30 FR FR837195A patent/FR564M/fr active Active
Also Published As
Publication number | Publication date |
---|---|
NL106036C (en) | 1963-09-16 |
FR564M (en) | 1961-06-05 |
BE579900A (en) | 1959-10-16 |
DK118874B (en) | 1970-10-19 |
GB928301A (en) | 1963-06-12 |
GB928302A (en) | 1963-06-12 |
CH386415A (en) | 1965-01-15 |
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